Method of operation utilizing venting for processing of blood to remove pathogen cells therein

ABSTRACT

An apparatus for locating and venting pathogen cells in blood. A cassette has a plurality of thin holding chambers that are filled with blood drawn from a patient. A light source illuminates each of the holding chambers and passes light to an underlying sensor array such that the cells in the blood produce shadow images of the cells in the sensor array. A processor performs pattern recognition to identify and locate the pathogen cells by use of an image library. After the pathogen cells are located, a pump is operated to move the identified cells to a processing zone. When each identified cell reaches the processing zone, a control voltage is generated to open a valve to vent the identified pathogen cells. The pump refills the cassette holding chambers, returns the processed blood to the patient, and the procedure is repeated for a treatment time period.

CROSS REFERENCE TO RELATED APPLICATIONS

Applicants have concurrently filed additional applications related tothe subject matter of the present application. These are: Ser. No.17/814,536 filed Jul. 25, 2022; Ser. No. 17/814,537 filed Jul. 25, 2022;Ser. No. 17/814,538 filed Jul. 25, 2022; Ser. No. 17/814,539 filed Jul.25, 2022; Ser. No. 17/814,541 filed Jul. 25, 2022; Ser. No. 17/814,542filed Jul. 25, 2022; Ser. No. 17/814,543 filed Jul. 25, 2022; Ser. No.17/814,545 filed Jul. 25, 2022; Ser. No. 17/814,546 filed Jul. 25, 2022;Ser. No. 17/814,547 filed Jul. 25, 2022; and Ser. No. 17/814,549 filedJul. 25, 2022.

BACKGROUND Field of the Invention

The present invention is in the field of biotechnology, semiconductortechnology and the medical field of treating individuals who have aninfection of pathogen cells in the bloodstream.

Description of the Related Art

The presence of bacteria in human blood is a serious condition termed“bacteremia”. This condition can cause an infection that spreads throughthe bloodstream. This can also be termed “septicemia” which is definedas the invasion and persistence of pathogenic bacteria in thebloodstream. Such an infection can lead to a condition termed “sepsis”which is the body's reaction to the infection. Sepsis is a seriouscondition that can cause intense sickness including shock, and in somecases, can lead to the death of the infected person. A common pathogenicbacterium causing such infection is E. coli., but infections can also becaused by other pathogenic bacteria and organisms such as the fungusCandida auris. The usual treatment for the patient is the application ofantibiotics to try to kill the pathogenic cells in the bloodstream.However, this treatment is not successful for many patients with abloodstream infection.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present invention and theadvantages thereof, reference is now made to the following descriptiontaken in conjunction with the accompanying drawings in which:

FIG. 1 is a perspective view of an overall system which includes anoperational unit and a system control unit,

FIG. 2 is a perspective view showing the interior of the enclosure 11shown in FIG. 1 ,

FIG. 3 is an elevation, section view of components inside theoperational unit shown in FIG. 1 ,

FIG. 4 is a plan view of the compression plate 51 shown in FIG. 3 ,

FIG. 5 is a bottom view of the light source shown in FIG. 3 with anarray of light generators,

FIG. 6 is an elevation, sectional view of a collimated beam lightgenerator, as shown in FIG. 5 ,

FIG. 7 is an elevation section view of the cassette 58 shown in FIG. 3 ,

FIG. 8 is a functional block diagram including additional components forthe system shown in FIG. 1 ,

FIG. 9 is a bottom view of the primary blood flow through the cassette58 shown in FIG. 3 ,

FIG. 10 is a section view along line 10-10 in FIG. 9 ,

FIG. 11 is a section view along line 11-11 in FIG. 9 ,

FIG. 12 is a is a section view along line 12-12 of FIG. 9 ,

FIG. 13 is a partial cutaway view of cassette 58, pump 62 and flow lines22 and 24 shown in FIG. 3 ,

FIG. 14 is a bottom, planar view of the middle layer of the cassette 58,shown in FIG. 3 illustrating the flow of blood through the inputmanifold channels, holding chambers and output manifold channels,

FIG. 15 is a view of a cassette 58 holding chamber having a plurality ofparallel ridges therein and multiple zones,

FIG. 16 is a section view of a portion of the cassette chamber shown inFIG. 15 showing a channel valve assembly and a vent line valve assembly,

FIG. 17 is a top view of a top view of a valve block shown in FIG. 15 ,

FIGS. 18A and 18B are section views of a valve assembly in the open andclosed positions,

FIG. 19 is a partial bottom view of the middle layer of the cassette 58,

FIG. 20 is a partial top view of the top surface of the cassette shownin FIG. 16 ,

FIG. 21 is an electrical schematic block diagram of the chamber drivershown in FIG. 17 ,

FIG. 22 is a top view of the top layer of the cassette 58 illustratingvent lines,

FIG. 23 is an illustration of a vent line and sump in association withcassette 58,

FIG. 24 is a partial electrical block diagram of the system shown inFIG. 1 ,

FIG. 25 is a top view of a light sensor array with control and datalines,

FIG. 26 is an electrical schematic of a 3T image sensor cell,

FIG. 27 is an electrical schematic of a 4T image sensor cell,

FIG. 28 is a top view of a layout of an image sensor cell,

FIG. 29 is a section view of a layout of an image sensor cell,

FIG. 30 is an illustration of cassette chamber zones used for physicalcalibration,

FIG. 31 is an illustration of a cassette chamber zone with a calibrationmarker,

FIG. 32 is an illustration of a portion of a sensor array illustratingphysical calibration,

FIGS. 33A and 33B are a flow diagram illustrating a light sourceamplitude calibration process,

FIG. 34 is a set of pathogen cell image views for pattern recognition,

FIG. 35 is a set of red blood cell images for pattern recognition,

FIG. 36 is a set of white blood cell images for pattern recognition,

FIG. 37 is a set of platelet cell images for pattern recognition,

FIG. 38 is an illustration of blood flow in chamber channels for celltravel time calibration,

FIG. 39 is a travel time versus fluid velocity chart for cell traveltime calibration,

FIGS. 40A, 40B and 40C are a logic flow diagram illustrating a traveltime calibration process,

FIGS. 41A and 41B are a logic flow diagram illustrating an operationalprocess to identify and locate pathogen cells and to move the identifiedcells to a processing zone in a chamber for venting to a sump, and

FIG. 42 is a diagram of electrical waveforms applied to valves in theprocessing zone of a chamber for selectively opening and closing thevalves to vent identified pathogen cells to a sump.

SUMMARY OF THE INVENTION

An embodiment of the present invention comprises an apparatus for firstexamining blood by imaging a first quantity of blood in a chamber toidentify and locate pathogen cells in this quantity of blood. Thepathogen cells thus identified are moved to a processing zone of thechamber and are then vented through a valve and transferred to a sump.The first quantity of blood, now processed, is then replaced withmultiple subsequent quantities of blood and the process of identifying,locating, moving and venting pathogen cells is repeated for eachquantity of blood. After these processing operations are performedrepeatedly over a period of time, the count of pathogen cells in thepatient blood is decreased.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is an apparatus for identifying pathogen cells inblood and venting the identified cells to reduce the count of such cellsin the blood and thereby potentially reducing the harmful effect of thepathogen cells.

Referring now to FIG. 1 , there is shown a system for processing bloodwhich identifies and determines locations of individual pathogen cellsin blood and then venting the identified cells to a sump.

The principal operations performed with the blood are carried out in anoperational unit 10 which is connected by a data and control cable 12 toa system controller 14 which can be, for example, a laptop computer orcomputer work station. The operational unit 10 receives electrical powervia a power line 16.

The operational unit 10 is connected to a patient 18 by means of atwo-lumen (two fluid channels) catheter 20. The patient 18 can bereclined on a horizontal surface. In this example, the catheter 20 isinserted into an artery in the leg of patient 18 to both receive bloodfrom the patient and return blood to the patient. The catheter 20 hasone lumen thereof connected to a blood input line 22 which is connectedto operational unit 10 and has a second lumen connected to a bloodreturn line 24 which is also connected to the operational unit 10. Theblood of patient 18 flows into the catheter 20, through input line 22 tothe operational unit 10 and from the operational unit 10 through thereturn line 24 and catheter 20 back to the patient 18. A catheter, suchas 20, is described in U.S. Pat. No. 6,872,198 issued Mar. 25, 2005which patent is incorporated herein by reference in its entirety.

Within the operational unit 10 the blood is imaged to identify andlocate pathogenic cells in the blood followed by venting the locatedpathogenic cells to a sump outside of the unit 10. This processcontinues over a period of time with a flow of blood from the patientfor the purpose of reducing the number of pathogenic cells in thepatient's blood.

The operational unit 10 includes an enclosure 11 having a top lid 11 awhich can be opened by use of a handle 11 b which rotates the lid 11 aon hinges 11 c.

Further referring to FIG. 1 , there is included a sump 25 that iscoupled via a drain line 45 to the interior of the unit 10. The sump 25receives blood fluid that has been vented from the blood flow in theoperational unit 10. The system shown in FIG. 1 further includes aheater/cooler thermal control 26 which provides temperature-controlledair through a duct 27 to within the enclosure 11.

The interior of the enclosure 11, shown in FIG. 1 , is illustrated inFIG. 2 without operational components. A set of four rods 30, 32, 34 and36 are mounted on the interior bottom surface of the enclosure 11. Theserods project upward, perpendicular to the bottom surface of theenclosure 11. The top end of each of the rods 30, 32, 34 and 36 arethreaded to receive respective nuts 38, 40, 42 and 44. The nuts 38, 40,42 and 44, when mounted on the corresponding rods, engage the topsurface of a compression plate 51 shown in FIGS. 3 and 4 . The enclosure11 can include a thermostat and be connected to an air heater/coolerthermal control unit 25 (see FIG. 1 and FIG. 8 ) to maintain theinterior of the enclosure 11 within a selected temperature range toavoid thermal damage to the blood in the enclosure 11. The enclosure 11has an opening 46 for passage therethrough of flow tubes and electricalconductors.

An embodiment of the present invention is shown in FIG. 1 , anddescribed in the corresponding text, with specific internal components50 of an operational unit 10 as shown in FIG. 3 . The operational unit10 has multiple components 50 inside the enclosure 11. These componentsinclude the compression plate 51 and a light source 54. The unit 50further includes a cassette 58 and an imager and processor unit 60. Line22 extends through a pump 62 to the input of the cassette 58. Pump 62draws blood from patient 18 through input line 22 into the operationalunit 10 and the blood leaves unit 10 through return line 24 and throughcatheter 20 back to patient 18. The components 54, 58 and 60 have planarconfigurations and, in operation, are pressed together with limitedspacing between them and secured by the nuts 38, 40, 42 and 44 to limitrelative movement. The return line 24 is connected to the output port ofcassette 58 and does not pass through the pump 62.

The compression plate 51 is shown in FIG. 4 . Plate 51 includes holes72, 74, 76 and 78 which are positioned to receive the respective rods30, 32, 34 and 36, see FIG. 2 . All of the elements 51, 54, 58 and 60are provided with colinear holes for receiving the rods 30, 32, 34 and36. When the nuts 38, 40, 42 and 44 are affixed to the rods 30, 32, 34and 36, with all of the noted components 50 (see FIG. 3 ) in place andhaving the rods 30, 32, 34 and 36 passing therethrough, the nuts aretightened on the rods to cause the compression plate 51 to apply forceto the stacked elements 51, 54, 58 and 60 to clamp them together andsubstantially limit relative movement, either horizontally orvertically, between these components.

A planar, bottom view of the light source 54 is shown in FIG. 5 . Source54 includes a 5×6 array 68 of light generators, which includes a lightgenerator 70 which is representative of all of the light generators inthe array 68. Each of the light generators, including 70, produces acollimated beam of light directed perpendicular to the cassette 58. Thelight generator 70 is further shown in an elevation view in FIG. 6 .Light source 54 includes holes 71, 73, 75 and 77 for receiving the rods30, 32, 34 and 36.

Collimated light sources are well known in the art. Multiple embodimentsof collimated light source generators are usable with the presentinvention. A collimated light generator is described in U.S. Pat. No.7,758,208 filed Dec. 26, 2007 which patent is incorporated herein byreference in its entirety.

Referring to FIG. 6 , the light generator 70 includes a light engine 80,an extraction lens 82, a collimator lens 84, a collimator lens 86, alenslet array 88, a profile reflector 90, a secondary lenslet array 92and a secondary collimator lens 94. The light generator 70 produces acollimated beam of light 96.

The cassette 58 is shown in an elevation section view in FIG. 7 .Cassette 58 comprises a top layer 134, a middle layer 136 and a bottomlayer 138. After fabrication as separate layers, the layers 134, 136 and138 are bonded together to form the cassette 58. All of these layers aremade of a transparent, non-electrical-conducting material, such as apolymer plastic.

The operational unit 10, shown in FIG. 1 , is further shown in FIG. 8with additional operational components. On the interior of enclosure 11there is the light source 54, cassette 58, and imager and processor unit60. Further included is a power supply 102 which receives power fromline 16 and provides power via power cable 85 to the processor unit 60,the light source 54 and the cassette 58. A temperature sensor 91 ismounted on the cassette 58 to measure the temperature of the cassette58. The temperature sensor 91 is connected to the system controller 14via a cable 95 to provide a temperature measurement of the cassette 58to the controller 14. A thermal control 25 is coupled by cable 28 to thecontroller 14. Cable 28 can be included with cable 12. The controller 14measures the temperature of the cassette 58 by the temperature sensor 91and activates the thermal control unit 26 to provide warmer air orcooler air to within the enclosure 11 via a duct 27 to drive thetemperature of the cassette 58 to a selected temperature, for example,typical human body temperature.

The above embodiment in FIG. 8 has a power line that is directlyconnected to the cassette 58. An alternative configuration has a lightpower transmitter on the unit 60 for each chamber of the cassette 58. Inthis alternative configuration there is adjacent to each chamber of thecassette 58 a light power receiver that receives the light power beamfrom the underlying transmitter and converts the light power toelectrical power that is provided to a chamber driver 318 shown in FIG.21 . By use of the light power transmission, there is no requirement tohave any power electrical connection to the cassette 58. The unitcontrols the light source 54 via a line 52. Alternative methods to theuse of light for transmission of power are power transmission usingelectrostatic or magnetic technology.

The cassette 58 has an array of holding chambers. One embodiment of thecassette 58 has an array of 30 holding chambers, as shown in FIG. 9 .This is a top-down view of layer 136. The chambers and flow lines shownare molded into the bottom region of layer 136. The cassette 58, asshown in FIG. 9 for an embodiment of the invention, has 30 holdingchambers 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206,208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234,236, 238, 240 and 242. The cassette 58 input manifold comprisesdistribution line 140 and chamber input lines 142, 144, 146, 148, 150and 152. The output manifold comprises chamber output lines 158, 160,162, 164, 166 and 168, the collection line 180 and the return line 182.This manifold configuration provides approximately the same blood flowpath distance from the input of line 140 to the output of line 182 forthe blood flowing through each of the holding chambers. Thisconfiguration contributes to a more uniform flow of blood through theholding chambers and more uniform fluid flow pressure gradient throughthe cassette 58. The bottom layer 138 forms a closing surface for all ofthe chambers and lines in the layer 136. See FIG. 7 .

Input line 142 supplies blood to each of the chambers 184, 186, 188,190, 192. Each chamber in cassette 58 can have, for example, an Xdimension of 2 centimeters, a Y dimension of 2 centimeters, and athickness (Z dimension) in the range of 8-12 microns. An example valueis 8 microns. A selected range of thickness is 10 microns or less. Thefacing area of each chamber is therefore 4 square centimeters. Theopening width from the input line 142 into chamber 184 is the same asthe Y dimension of the chamber, in this example, 2 centimeters.Likewise, the output from each chamber, such as 184, is the Y dimension,in this example, 2 centimeters. A chamber, as viewed at the input, isrelatively wide (2 centimeters) and relatively thin (8 microns). Thisconfiguration is the same for all of the remaining holding chambers incassette 58. Each of the chambers has an input port and an output port.See FIG. 15 . Between the input line, such as 142, and the input port toa chamber, such as 184, there is a flow path having the same width andheight as the chamber and a length of, for example, 0.1 to 0.4centimeters. There is a similar flow path at the output port of eachchamber. These flow paths can assist in providing a uniform fluid flowthrough the chamber. These flow paths are shown in FIG. 15 as flow pathregions 251 and 253.

Further referring to FIG. 9 , the blood fluid leaves the holdingchambers 184-242 and moves into the corresponding connected chamberoutput lines 158-168. The exit passageway from a chamber is the sameconfiguration as the input passageway, that is, for this embodiment, theexit passageway is 2 centimeters wide and 8 microns thick. The bloodflows through the output lines 158-168 into the collection line 180 andthen into the return line 182.

As a flow example, referring to FIG. 9 , blood is driven intodistribution line 140 and then into chamber input line 150 and at thefar end of this line, into chamber 232. After the blood in this chamberis processed, the blood in chamber 232 is driven out of the chamber bypump 62 into the chamber output line 166 and from the end of line 166into the collection line 180. From line 180, the blood flows into thereturn line 182 and then into the blood return line 24. The bloodtravels through the cassette input manifold to all of the chambers andreturns from all of the chambers through the cassette output manifold.

Further referring to FIG. 9 , the cassette 58 is provided with alignmentholes 252, 254, 256 and 258. The cassette 58 is lowered onto thecorresponding upward facing rods 30, 32, 34 and 36 (See FIG. 2 ),mounted inside the operational unit 10, which pass through correspondingaligned holes in the imager and processor unit 60 (See FIG. 3 ). Therods pass through the holes in the cassette 58 to provide alignment ofthe cassette 58 with the imager and processor unit 60. The light source54 (FIG. 3 ) has corresponding alignment holes to receive the rods 30,32, 34 and 36 so that the imager and processor unit 60, cassette 58, andlight source 54 are aligned with each other. The top ends of the rodsare threaded so that nuts 38, 40, 42 and 44 (See FIG. 2 ) can be appliedto each rod and tightened so that all three of these units are pressedtogether and held in alignment with each other.

FIG. 9 shows a top, planar view of the middle layer 136 of cassette 58.Each of the holding chambers 184-242 comprises a recessed region intothe bottom side of the middle layer 136. Each chamber recess, in oneembodiment, is approximately 8 microns thick, 2 centimeters long and 2centimeters wide. Referring to FIG. 10 , each holding chamber includes aplurality of long, thin ridges 248, illustrated as horizontal lines ineach chamber in FIG. 9 , and shown in detail in FIG. 10 , which is asection view along line 10-10 of a representative holding chamber 196 inFIG. 9 . The ridges 248 are formed as a part of the middle layer 136.Example dimensions for a holding chamber and the ridges 248 are shown inFIG. 10 . The holding chamber 196 is approximately 2 centimeters wide,as shown, and 2 centimeters long, not shown. The ridges 248 extend forthe length (2 centimeters) of the holding chamber 196. Each ridge, inone embodiment, is, for example, 8 microns high and 4 microns wide. Theheight of the ridges matches the thickness of a chamber. In thisembodiment, each of the holding chambers 184-242, has a thickness of,for example, 8 microns. In this example, there are 20 of the elongateridges spaced in parallel across a distance of 2 centimeters. Therefore,the spacing (channels) between the ridges is approximately 950 microns.Each of the ridges 248 serves as a support for the bottom layer 138 (SeeFIG. 7 ) which is pressed against the top of the ridges 248 shown inFIG. 10 . The ridges 248 also function as spacers to maintain anessentially uniform 8-micron thickness over all of the area of eachholding chamber. The ridges 248, in the illustrated configuration,further form 21 flow channels through the chamber. There can be moreridges to make the channels narrower. These channels reduce the lateralflow of blood in a chamber and support a more straight-through fluidflow from the input to the output of each chamber.

FIG. 11 is a section view taken along lines 11-11 in FIG. 9 in thedistribution line 140. The distribution line flow channel has aflat-bottom with semi-circular cross section that has been pressed ormolded into the middle layer 136. The flat, and sealing, surface of theflow line 140 is provided by the top surface of the bottom layer 138.FIG. 12 is a section view take along lines 12-12 in FIG. 9 located inthe input line 144. It is likewise pressed or molded into the middlelayer 136 and covered with the bottom layer 138. The cross-sectionalarea of line 144 at 12-12 is substantially smaller than that of line 140at 11-11. There is a greater volume of blood flow through line 140 at11-11 than through line 144 at 12-12.

All of the layers 134, 136 and 138 are fabricated of, for example,transparent polycarbonate plastic, produced by a pressing or moldingprocess such as described in U.S. Pat. No. 6,998,076 issued Feb. 14,2006 which patent is incorporated herein by reference in its entirety.As an example embodiment, the top layer 134 and middle layer 136 caneach be approximately 2-3 millimeters thick, bottom layer 138 can be1-1.5 millimeters thick for a total cassette 58 thickness ofapproximately 5-7.5 millimeters.

The middle layer 136 of cassette 58 can be fabricated by the use ofpolycarbonate injection molding and a metal mold. An etched glass masteris used to form the metal stamping mold. To make the glass master, theprocess starts with a sheet of glass. The sheet of glass, approximately5 millimeters thick, is sequentially masked with photoresist patterns(as done in the manufacture of semiconductors) and an acid is applied toetch the non-masked portions. The acid removes a portion of the glass,producing a recessed pattern in the glass and forming the distributionlines and holding chambers. The final 8 micron etch can be done byplasma etching to produce more vertical sidewalls on the ridges 248.After removing the last photoresist, the surface of the glass mold istreated with a mold-release component, and then is covered with a layerof nickel or silver using an electrodeless plating method. Sputteringcan be used, or a colloidal silver method can be used. Then, nickel iselectroplated over the surface to a thickness of perhaps 0.5 cm forminga metal mold. After separating the electroformed nickel mold from theglass master, the metal mold has raised areas corresponding to thedistribution lines and holding chambers. This process is similar to themanufacturing process for phonograph records, compact discs and DVDs asshown in U.S. Pat. No. 6,998,076 noted above. Heated polycarbonateinjection molding is used with the metal mold to form the recessed flowchannels and holding chambers in what will be the top layer of thecassette. The polycarbonate flows around the raised areas in the metalmold. When the metal mold and polycarbonate are cooled, thepolycarbonate sheet is removed and it has the configuration for the toplayer 13, as shown in FIGS. 9-12 .

Alternately, a metal mold can be machined or etched to have theconfiguration to produce the cassette middle layer 136 by applying asheet of polycarbonate to the mold, heating both the mold and the sheetand allowing the polycarbonate to flow into the metal mold to producethe desired shape for the cassette 58. Top layer 134 is fabricated asdescribed above for middle layer 136. The bottom layer 138 is a flatsheet of the same plastic material as the other layers.

The cassette 58 can be fabricated of a plastic with an includedanti-thrombogenic material to reduce the possible adhering of blood thatcontacts interior surfaces of the cassette 58. Such a material isdescribed in U.S. Pat. No. 6,127,507 issued on Oct. 3, 2000, whichpatent is incorporated herein by reference in its entirety.

FIG. 13 is an illustration of the cassette 58 together with theperistaltic pump 62 and the blood flow lines. The blood input line 22 ispositioned in the pump 62 between pump rollers 62 a and 62 b and acircular pump pressure plate 66. The rollers rotate about a center shaftand compress the line 22 against the interior curved surface of plate66. The rollers apply sufficient force to close the flexible line 22and, as they rotate, they force blood to flow through the line 22 towardthe cassette 58. The pump 62 can be started and stopped as needed topump blood to the cassette 58. After the blood has passed through thecassette 58, it flows through the return line 24 to the catheter 20 andthen back to the patient 18. The structure and operation of aperistaltic pump is well known in the art, particularly in the field ofkidney dialysis.

The flow of blood through the lines and chambers of the cassette 58 isshown in FIG. 14 . This is a top view illustrating the bottom of layer136. Blood enters the input line 22 into distribution line 140 and issequentially distributed into the chamber input lines 142-152. Note thatas the volume of blood flowing through line 140 is decreased, the sizeof the line 140 is correspondingly decreased. Note that each of thedistribution lines 142-152 is tapered so the line size is decreased asthe amount of blood flowing in the line decreases. For example, bloodflowing in through input line 22 has a portion thereof directed intodistribution line 142 and a portion of that flow enters holding chamber186. As described previously, the chamber 186 is approximately 8 micronshigh and there are parallel ridges 248 that guide the blood in a uniformflow through the chamber 186. This substantially reduces transverseblood flow in a chamber. At the exit of chamber 186, the blood entersoutput line 158 where it joins the blood that has passed through chamber184. The blood from the chambers 184 and 186 flows through output line158 and is joined sequentially by the blood from chambers 188, 190 and192. The blood that has flowed through the chambers 184-192 then entersthe collection line 180. The blood from all of the holding chamberstravels into the collection line 180 from which it flows into thecassette 58 return line 182 to the blood return line 24.

Note in FIG. 14 that the configuration of flow lines and chambersprovides approximate the same travel distance for blood flowing througheach of the holding chambers 184-242. In each flow path, the blood flowsthrough or beside 10 holding chambers. For example, the blood flowthrough chamber 206 first passes chambers 184, 194 and 204 then flowsthrough chamber 206 and then passes chambers 208, 210, 212, 222, 232 and242, for a total distance of 10 chambers. This configuration of chambersand flow lines contributes to uniformity of blood flow and uniformity ofpressure gradient reduction for blood flow through the cassette 58.

Referring to FIG. 15 , there is shown a chamber 244, which isrepresentative of each of the chambers 184-242 described above. Thischamber 244 is formed in the plastic body of the middle layer 136,bottom side, of the cassette 58. (See FIG. 7 ). The layer 136 has moldedridges which are shown as a group 248 in FIG. 10 . The ridges in FIG. 10are shown as horizontal lines in the chamber. The chamber 244 issubdivided into an identification zone 246 and a processing zone 250. Aregion 171 of the processing zone 250 is shown in greater detail in FIG.16 . The flow path region 251 functions as an input port to the chamber244 and the flow path region 253 functions as an output port from thechamber 244.

In operation, blood flows through an input line into the identificationzone 246 where it is stopped and an image of this zone is produced by alight source which illuminates the chamber and cell shadow images aredetected by a light sensor array on the opposite side to produce amulti-pixel sensor image. The data from the sensor array iselectronically processed by pattern recognition using a referencelibrary of pathogen cell images to locate pathogen cells in the chamberidentification zone 246. After the pathogen cells have been located inthe channels of the chamber 244, a travel time is taken from a referencedatabase table to specify the travel time for each pathogen cell to avent line in the processing zone after the pump is started. The pump isstarted and when each travel time in each channel elapses, a voltage isapplied to open a valve in a vent line from the channel in theprocessing zone to vent the pathogen cell together with a limited amountof surrounding fluid. The blood continues to flow through the processingzone until all of the identified pathogen cells have passed into theprocessing zone and have been removed by selective venting. The bloodflow is then stopped and the process is repeated. Further structure ofthe processing zone is described below.

Referring to FIG. 16 , which is a detail view of a region 171 (See FIG.15 ) there is shown a section view of the cassette 58. A channel 272 isformed on the bottom surface of layer 136 located between two of theridges 248 shown in FIG. 10 , but not shown in FIG. 16 ). Fluid flowsfrom right to left in channel 272. A vertical channel vent line 277 inlayer 136 extends upward from channel 272 such that fluid can flow fromchannel 272 into vent line 277. The line 277 opens into a cassette ventline 274 that is molded in the bottom of top layer 134. Furtherreferring to FIG. 16 , there is a rectangular molded recess 280 in theupper surface of the layer 136. A valve block 282 is positioned inrecess 280. For each channel in the chamber 244 (FIG. 15 ) there is avertical channel, such as channel vent line 277 connecting to acorresponding cassette vent line, such as 274, in the upper layer 134.For channel 272 there is a valve assembly 287 in an opening 285 in thevalve block 282. Assembly 287 has a moveable element 290 which can bemoved through a hole 288 into a region 291 where the element 290 blocksthe flow of fluid through channel 272 downstream of the opening intochannel vent line 277. The valve assembly 287 has a driver 292 that iscoupled to the element 290 for selectively moving the element back andforth between an extended position in region 291 and a retractedposition in layer 136 which does not affect fluid flow in channel 272.The assembly 287 has an electric field generator 293 which produces aselectable field that is applied to the driver 292. The driver 292 canbe a magnet which is responsive to a first polarity field from generator293 to drive the element 290 into the region 291 and driver 292, inresponse to an opposite polarity field from generator 293 retracts theelement out of channel 272 into the hole 288. Assembly 287 is a flowchannel valve.

Still further referring to FIG. 16 , there is an opening 286 in valveblock 282 which has a valve assembly 294 in opening 286. The valveassembly 294 has a driver 296 coupled to a moveable element 297. Anelectric field generator 298 applies a selective electric field todriver 297 to move element 297 into a region 299 or to retract element297 from region 299. Assembly 294 is a vent valve.

In operation, after blood fluid in channel 272 has been imaged, the pump62 (FIG. 3 ) is activated to drive fluid through channel 272 towardvalve assemblies 287 and 294. At this time, valve element 290 isretracted and valve element 297 is extended to that no blood fluid flowsthrough channel vent line 277. When a total travel time period for adetected pathogen cell in channel 272 expires, the valve block 282drives valve assembly 287 to extend element 290 into position 291 toblock the flow of fluid and at the same time activates valve assembly294 to withdraw element 297 from blocking fluid flow through the channelvent line 277. The pump 62 drives a slug of blood fluid from channel 272into channel vent line 277 until the valve block activates the valveassemblies 287 and 294 to return corresponding elements to the originalpositions such that the blood fluid flow continues only through channel272 downstream from channel vent line 277. Thus, a slug of blood fluid,which includes a detected pathogen cell, is vented from the chamber 244and flows through a vent line into the sump 25 (FIG. 1 ). There are twovalve assemblies, as shown in FIG. 16 , for each channel of the chamber244 and for each chamber in the cassette 58.

The structure shown in FIG. 16 is representative for all of the channelsin each of the chambers in the cassette 58. Each chamber can havehundreds or even thousands of channels with the correspondingstructures.

The valve block 282 is shown in a top view in FIG. 17 . The block 282includes the chamber driver 318 which is further described in FIG. 21 .The driver 318 selectively activates each of a plurality of drive lines284. Each of the lines 284 comprises two conductors which are coupled toeach of chamber channel valve assemblies 275 and vent line valveassemblies 276. One of the channel valve assemblies 275 is valveassembly 287 and one of the vent channel assemblies 276 is valveassembly 294. See FIG. 16 .

Operation of a representative valve assembly 294 is shown in FIGS. 18Aand 18B. Assembly 294 is shown in the open position in FIG. 18A and inthe closed position in FIG. 18B. The driver 296 can be a magneticmaterial which interacts with the electric field produced by the fieldgenerator 298. The polarity of the field produced by generator 298determines the position of the driver 296 and therefore the positions ofthe valve element 297. Other types of physical actuators can similarlymove the element 297 into and out of the channel vent line 277.

The valve assembly 294 is a micro-actuator. There are numerous types ofmicro-actuators known in the art which can perform as a driver for thevalve assemblies 287 and 294. Examples of such micro-actuators aredescribed in U.S. Pat. No. 8,258,899, which issued Sep. 4, 2012 andwhich patent is incorporated herein by reference in its entirety.

FIG. 19 is a view of the bottom of the middle layer 136 of the cassette58. Channels 529, 530, 531, and 532 are formed between pairs of ridges533, 534, 535, 536 and 537. The channels 529, 530, 531 and 532 havechannel vent lines 538, 539, 540 and 541. The channels 529, 530, 531 and532 have respective openings 542, 543, 544, and 545 which receive valveelements which when extended block fluid flow through the correspondingchannel See FIG. 16 .

FIG. 20 (not shown to scale) illustrates the top of the middle layer136. The dashed boxes represent the locations of holding chambers, forexample, chambers 224, 234, 226, and 236 (See FIG. 9 ). Vent holes 235,225, 237 and 227 respectively vent fluid from holding chambers 234, 224,236 and 226. These vent holes are connected to cassette vent lines inthe layer 134 and these vent lines empty into the sump 25 via line 45.See FIG. 1 .

An electrical block diagram of the driver 318 is shown in FIG. 21 .Driver 318 is preferably an integrated circuit. The driver 318 includesa light data receiver 348 which receives pulsed light from an associatedprocessor, described below, with data defining the voltage signals to beapplied to the control lines for each valve in each of the channels inthe associated chamber. The light data receiver 348 provides a receivedsignal via a line 351 to a data receiver 352. The data receiver 352provides a digital data stream via a line 353 to a processor 354. Theprocessor 354 is coupled via a bus 355 to a multiplexor/driver 356.Driver 356 is electrically connected to the pads in a set of pads 320.Electrical power to operate the driver 318 is received as light by alight power receiver 349 (such as a photocell) and the electrical poweris provided through lines 350 to the power receiver and driver 357. Thelight for the receiver 349 is transmitted from a light power transmitter408 shown in FIG. 24 . The transmitter 408 receives power via a line 415which is coupled to the chamber processor 401. The power receiver driver357 provides electrical power to the data receiver 352 via a line 359,to the light data receiver 348 via a line 361, to the processor 354 viaa line 363 and to the multiplexor/driver 356 via a line 365. The driver318 also include a timer 360 connected to processor 364 via lines 322 toprovide clock and timing functions for the processor 364. Themultiplexor/driver 356 selectively drives lines 324 which arerespectively connected one for one to pads 320. Referring to FIG. 17 ,the pads 320 are respectively connected to lines 284 wherebymultiplexor/driver 356 is electrically coupled to each of the channelvalves 275 and vent valves 276. Each illustrated line to a valve is twoelectrical lines so as to provide a voltage difference. With thisconnection configuration, the chamber driver 318 can drive each of thechannel valves 275 and vent valves 276. The use of power transmission bylight eliminates the need for a physical power connection to thecassette 58. An alternative to the power transmission by light is aphysical power connection line to the cassette 58.

The flow of vented fluid from the chambers of a cassette 58 is shown inFIGS. 22 and 23 . A representative chamber 234 (See FIG. 9 ) has achamber exit vent line 453 that empties into a collection line 455 whichin turn empties into a cassette vent line 459. All of the chambers inthe cassette 58 empty into the vent line 459, which is connected to thedrain line 45 such that the vented fluid from all of the chambers of thecassette 58 are delivered to the sump 25 (See FIG. 1 and FIG. 23 ).Chambers 236 and 238 have respective vent lines 547 and 548 that emptyinto collection line 455. Chambers 224 and 214 have respective ventlines 549 and 546 that empty into vent lines 550 and 554 which in turnempty into vent line 459. Chambers 226 and 228 have vent lines 551 and552 that empty into vent line 550 which empties into vent line 550. InFIG. 23 , vent line 459 is coupled to drain line 45 to convey the ventedblood fluid to the sump 25.

There is one channel valve and one vent valve for each channel in eachchamber of the cassette 58. The collection of valve assemblies is in theprocessing zone 250 of chamber 244, shown in FIG. 15 .

FIG. 24 is an electrical block diagram of components in the systemillustrated in FIG. 1 with detailed structure shown for the imager andprocessor unit 60. The unit 60, in one embodiment, includes a printedcircuit board with components mounted on it. The system controller 14(See FIG. 1 ) is coupled via a cable 12 to the unit 60 by use of aconnector 391 and a cable 392 to a master controller 434. The controller434 can be, for example, a microprocessor, a dedicated gate array orother processing device. The controller 434 can activate and deactivatethe light source 54 and pump 62 via a cable 444. The master controller434 is connected via a cable 393 to an input/output (I/O) multiplexor394. The multiplexor 394 is connected to each of a plurality ofassemblies 395. In an embodiment, there is one of the assemblies 395 foreach of the chambers of the cassette 58, such as the 30 chambers 184-242shown in FIG. 9 . The master controller 434 can communicate via themultiplexor 394 to each of the assemblies 395 and can receivecommunication from each of the assemblies 395. Each assembly 395includes a light sensor 260 which is positioned below and aligned with acorresponding chamber in the group of chambers 184-242. Each lightsensor has an array of light sensitive pixels. See FIG. 25 . Themultiplexor 394 communicates with the assembly 395 via cables 396, 397and 398. There is a similar set of cables, such as printed circuit boardtraces, for each of the other assemblies in the unit 60. Each lightsensor array 260 is aligned with a corresponding holding chamber forreceiving light which has passed through the corresponding holdingchamber. The light sensor 260 array is positioned parallel to but offsetfrom the corresponding holding chamber.

Further in reference to FIG. 24 , each assembly 395 includes a memory399 which receives digital data from the light sensor 260 via a cable400 comprising data and control lines (See FIG. 25 ). When the lightsensor 260 has received light and has a data state for each pixeltherein, this data is transferred to the associated memory 399. Eachassembly 395 further includes a chamber processor 401 which has a databus 403 and control line 407 coupled to the memory 399. The processor401 can command that part or all of the data in memory 399 betransferred to the processor 401 to be processed. The master controller434 communicates via the multiplexor 394 and cable 396 to the chamberprocessor 401, the cable 397 to the light sensor 260 and cable 398 tothe memory 399. Each assembly 395 further includes a light datatransmitter 409, for example a modulated laser beam generator, connectedvia a data transmission and control cable 411 to processor 401. Receiver348 shown in FIG. 21 receives the light data.

As shown in FIG. 1 , the heater/cooler thermal control unit 26 iscontrolled by the system controller 14 through line 28.

Light data transmitter 409 sends data to the data light receiver 348 inthe chamber driver 318, see FIG. 21 .

Referring to FIG. 24 , unit 60 has holes 422, 430, 436 and 438 near thecorners of the unit for receiving the rods 30, 32, 34 and 36 shown inFIG. 2 .

An example of light sensor 260 array integrated circuit for use with thepresent invention is shown in FIG. 25 . A sensor array 260 includes anarray 262 of individual pixel cells, each pixel cell further describedbelow. The illustrated pixels are not to scale. Surrounding the array262 of pixel cells is circuitry termed control and I/O (Input and/orOutput) 264 which controls the operation of the sensor array 260 and thetransfer of pixel data collected by the sensor array 260. A group ofdata lines 266, for example 16 parallel lines, transfers pixel data fromthe pixel array 262 to an associated memory. A set of control and powerlines 268, for example 8 lines, controls the operation of the sensorarray 260 and provides power for operation of the sensor array 260circuitry. As further described below, the sensor array receives a resetsignal to set an initial charge state in each of the pixels. When thepixels are exposed to light, each pixel is discharged from the initialstate to a final state (the pixel data) depending on the amount of lightthat was received by the pixel. A command is sent through lines 268which causes the sensor array 260 to transfer the collected pixel datathrough one or more of the lines 266 to an associated memory.

As an example, the pixel array 262 can have a pixel size of 0.5 micronby 0.5 micron (square configuration) and the light sensitive array has asize of 2 centimeters by 2 centimeters. There is only one bit per pixel,either light or dark, therefore, the pixel data for one image is thesize of the number of pixels. These dimensions are exemplary only, and asensor array larger or smaller than array 262, as shown, may be used.

A circuit for each of the pixels in the array 260, can be any one ofmany types. A 3-T (three transistor) pixel circuit is shown in FIG. 26and a 4-T (four transistor) pixel circuit is shown in FIG. 27 .

Referring to FIG. 26 , a 3-T pixel circuit 300 includes a photodiode(PD) 302, a transfer transistor 306, a reset transistor 304, a drivetransistor 308 and a floating diffusion (FD) 310. A reset signal (RS) issent through a line 314 to the gate of reset transistor 304. A transfercontrol signal (TG) is provided through a line 316 to the gate oftransistor 306. The image data produced by pixel circuit 300 istransmitted through column line 312.

In operation, the pixel circuit 300 is initially reset by turningtransistor 304 (RX) on to charge node FD 310 to VDD. Next the TG signalturns on TX transistor 306 which couples the node FD to the cathode ofphotodiode 302. Upon receiving light at the photodiode 302, the diodereverse conducts and discharges node FD dependent upon the amount oflight received by the diode. The charge on node FD drives the transistor308 (DX) which applies a corresponding current to the column line 302.

A 4-T pixel circuit 326 is shown in FIG. 27 . This circuit has aphotodiode (PD) 328, a reset transistor 330 (RX), a transfer transistor332 (TX), a drive transistor 334 (DX), and a select transistor 336 (SX).A floating diffusion 338 (FD) is connected to the gate of transistor334. Transistor 330 (RX) receives a reset signal through line 342.Transistor 332 (TX) receives a drive signal (TG) through a line 344.Transistor 336 (SX) receives at its gate a select control signal (SEL)via a line 346.

The pixel data, which is the measured light, is sent through the columnlines 312 and 340 in FIGS. 26 and 27 . At the end of these lines thereis an analog to digital converter to produce a high or low, 1 or 0,digital signal. This is essentially a threshold detection. Each pixeldata represents dark or light, depending on how much light was receivedat the pixel.

Operation of the pixel circuit 326 (FIG. 27 ) begins with receipt of areset (RS) signal at transistor 330 to charge node FD 338 to VDD. Next,the transfer control signal (TG) turns on transistor 332 to couple thecathode of photodiode 328 to node FD. When the photodiode 328 receiveslight, charge is drawn from node FD to reduce the voltage on node FD,which drives the gate of transistor 334 (DX). For readout of data fromthe pixel, signal SEL is applied to turn on transistor 336 (SX) tocouple transistor 334 (DX) to the column line 340. The column line 340is sequentially used to transfer data from all of the pixels connectedto the column line.

FIGS. 28 and 29 illustrate a physical integrated circuit structure forimplementing the 4-T pixel shown in FIG. 27 . Layout 358 in FIG. 28 is atop view. A unit pixel area 362 is the area occupied by the pixelstructure. A deep trench isolation (DTI) region 364 serves to isolateeach pixel from surrounding pixels. Active area 366 is the area of thepixel which receives light. A shallow trench isolation (STI) 368separates active elements of the pixel. First border 370, second border378 and third border 380 serve to isolate elements of the pixel circuitto reduce noise. 372 is a ground element. 374 is a transfer gate. 376 isa floating diffusion. 382 is a p-well. 384 is a p-well. 386 is the drivetransistor gate. 388 is the select transistor gate and 390 is the resettransistor gate.

FIG. 29 is a section view layout 402 along line 29-29 of the structureshown in FIG. 28 . The common elements in FIGS. 39 and 40 have the samereference numerals. Element 404 is an oxide isolating layer, 405 is aborder, 406 is a polysilicon isolation layer and 410 is a photodiode inconjunction with the epitaxial layer 412. Element 414 is ananti-reflection layer. 420 is a gate isolation layer. 424 is a floatingdiffusion (FD 338 in FIG. 27 ). Light, shown by the upward pointingvertical arrows in FIG. 29 , produced by the light source (54 in FIG. 3), is transmitted to the pixel structure and in particular to thephotodiode for measuring the light received by this one pixel.

Referring to FIGS. 30, 31 and 32 , there is shown physical calibrationapparatus and a process for the alignment of a cassette chamber with theunderlying light sensor. A segment 416 of a chamber, such as any ofchambers 184-242 (FIG. 9 ) is subdivided into a set of areas, which, inthis example, each area has a size of 100 microns by 100 microns. Area418 is near the corner of a cassette chamber, and FIG. 31 illustrates amiddle region of the area 418. A light blocking calibration marker 419is positioned approximately in the middle of area 418. The upper leftcorner of the marker 419 is at the position of 150 microns horizontaland 150 microns vertical. The marker 419 is printed on the interiorsurface of the cassette chamber. The marker, in this example, has aunique L-shape which is 2 microns long, 1 micron wide and the body is0.50 micron wide. This shape can be readily identified in patternrecognition operation in a processor. FIG. 32 illustrates a region ofthe light sensor beneath the chamber having the marker 419. If thechamber and underlying light sensor were perfectly aligned, the shadowimage of the chamber marker 419 would be at the same position in thelight sensor, as shown by the dotted marker outline 421. But, if thechamber and light sensor are not in perfect alignment, the marker 419could produce a shadow image 423 which is offset from the dotted markeroutline 421. In the illustrated example, the shadow image 423 is offsetby 6 microns to the right and 8 microns down. Thus, for the area 418,the alignment correction is (−6, −8). Thus, for any image in the 418area for the light sensor, the position determined in the light sensoris adjusted by −6 microns horizontally and −8 microns vertically. Eachof the areas of the cassette chamber is provided with a printed marker,such as 419 and the shadow image of each marker in the light sensor isdetermined. A physical calibration table is prepared having a pair ofcorrection numbers for each area, such as 418, of the cassette chamber.The corrected position from the sensor array is the actual position inthe overlying cassette holding chamber.

Referring to FIGS. 25 and 31-32 , the sensor array can be divided intocalibrations zones. For a 2 cm by 2 cm sensor array, each calibrationzone can be, for example, 100 microns by 100 microns. With these sizes,the array 262 has 4×10⁴ calibration zones. If the calibration zone islarger, there will be fewer calibration zones in the sensor array. Eachcalibration zone can be calibrated, as described, and the calibrationvalues can be different between calibration zones. This compensates fornonlinearities in alignment across the sensor array 262.

The chamber processors, such as 401 shown in FIG. 24 , have oneprocessor used with each sensor array, can be, for example, amicrocomputer, a graphic processor or a custom gate array. The mastercontroller can be, for example, a microcomputer or a custom gate array.

The 30 sensor arrays (See FIGS. 9 and 24 ) are each aligned with aholding chamber in cassette 58. There is a one-to-one relationship. Forexample, holding chamber 184 (FIG. 9 ) is positioned over and alignedwith a light sensor such as 260 (FIG. 24 ). Each of the remainingholding chambers (FIG. 9 ) of the cassette 58 is likewise located overand aligned with a corresponding sensor array (See FIG. 24 )

Operation of the apparatus described herein can include an initialcalibration of the light energy produced from the light source 54 to besufficient to activate, but not overdrive, the individual pixels in thelight sensors 260 shown in FIGS. 24 and 25 . Also referring to FIG. 3 ,as directed by the master controller 434, after receiving an energycalibration command from the system controller 14, the energycalibration process first resets all of the pixels in all of the sensorarrays 260. Next, it activates all of the pixels in all of the sensorarrays and then activates the light generation from the light generator54 for a selected time and intensity. The pixels in the light sensorsare then deactivated, the pixel data transferred to the correspondingmemory and the processor activated to run a light energy calibrationroutine. If the light energy is sufficient, all of the pixels will belight, that is, no dark pixels since there is nothing in the cassetteholding chambers during this calibration process. The markers in thechambers are excluded. The processor counts the number of dark pixels.The master controller polls all of the chamber processors to collect thenumber of dark pixels. If the number of dark pixels exceeds a presetthreshold, such as 0.001%, the calibration process is repeated and theselected time is incrementally increased until the number of dark pixelsis less than the preset threshold. If the initial measurement shows thenumber of dark pixels to be less than the present threshold, the processis repeated with shorter light activation times until the threshold iscrossed and the last lower value is selected as the light activationtime. The light energy can be varied by changing the length of time thelight is on, or by varying the intensity of the light. In either case, alight activation value, either time or intensity, will be produced.

Light energy calibration can also be performed after the blood holdingchambers have been filled as shown by the steps in FIGS. 33A and 33B.The system controller 14 initiates the filled chambers light energycalibration operation by sending a command to the master controller 434.See step 568. The master controller 434 receives the calibration commandfrom the system controller at step 569. Referring to FIG. 24 , thecontroller 434 drives the pump 62 to fill the holding chambers incassette 58 (FIGS. 3 and 9 ). See step 570. Next, in step 572, thecontroller 434 sends a reset command to each of the light sensors 260.After the pixels in each sensor are reset, the controller 434 commands(step 573) each light sensor array to be activated. Next, in step 574the light generator 54 is activated for a period of time X. Thecontroller 434, in step 575, deactivates all of the light sensor arrays,and in step 576 commands each sensor array to download its pixel data tothe corresponding memory. Next, in step 577, the controller commandseach chamber processor associated with a sensor array to (step 578)access the pixel data in the corresponding memory and perform a lightcalibration process in which the number of light transitions betweenadjacent pixels is counted. The transition can be either light to darkor dark to light. Each pixel has four adjacent pixels and each possibletransition is examined. For example, a dark pixel surrounded by fourlight pixels produces four transitions. In step 588, the controller 434then collects the pixel transition count from each processor and addsthem together to produce a total transition count corresponding to theperiod of time the light generator was on. In step 589, the mastercontroller produces a table of light durations as shown below inTable 1. Next the above process is repeated with an incrementally longerperiod of time for the operation of the light generator. The number oftransitions for this period is determined and recorded. Next, inquestion step 590, it is determined if the peak value of the number oflight transitions has been passed. This is selected, for example, byhaving 100 sequential transition counts lower than a precedingtransition count. If the response to question step 590 is “NO”, in step592, the value of X is increased by a selected increment, and control isreturned to step 572. This process is repeated until a peak oftransition number is reached, as noted. If the response to question step590 is “YES”, the master controller 434, in step 594 sends the completedtable of light duration and count of pixel transitions to the systemcontroller 14. This calibration process terminates at STOP step 596. Anexample of such data is as follows. The light energy value is a relativemeasure and the Pixel Transitions number is a truncated value, such asbillions of transitions.

TABLE 1 Relative Light Energy Pixel Transitions 1 50 2 65 3 85 4 100 5120 6 140 7 150 8 165 9 160 10 150 11 135 12 125 13 115 14 105 15 90As seen in the above data listing in Table 1, the optimum light energyvalue is “8” which corresponds to the pixel transition value “165”. Thenumber of pixel transitions is an indicator of the quantity of imageinformation present in the pixel data and is likely the best image data.Therefore, for this instance of testing, the light energy should be setto the relative level of “8” for the process described herein toidentify and locate pathogen cells in the blood. As noted above, thelight energy can be varied by time duration or by the intensity of thelight produced.

A pathogen cell, together with a measurement scale, is shown in multiplepositions in FIG. 34 . E. coli is a rod-shaped bacterium. The dimensionsfor this bacterium can vary but some species can be in the range of 2-3microns long and 0.25 to 1 micron thick. In FIG. 34 , there is shown inthe left column an E. coli bacterium cell 600. The left column shows anactual view of a cell and the two right columns show shadow images thatcan be produced by that view of the cell by the sensor arrays (FIG. 25). These views are based on a system as described with 0.50 micron by0.50-micron sensor array pixels. The right two columns show shadowimages produced by the corresponding cell in the left column. The cell600 is shown at multiple rotations along a vertical axis with angles of0, 15, 30, 45, 60, 75 and 90 degrees. These multiple views are requiredbecause the cell could be at any rotation position as it is viewed in aholding chamber. The right two columns (a) and (b) represent possiblevariations on the image produced by the cell positioned at the indicatedrotation. Images 602 and 604 can be produced by cell 600 at rotation of0 degrees. These can differ due to edge effects and small thresholddifferences in pixel sensors. Images 606 and 608 could be produced forrotation 15 degrees, 610 and 612 for rotation 30 degrees, 614 and 616for 45 degrees, 618 and 620 for 60 degrees, 622 and 624 for 75 degreesand 626 and 628 for 90 degrees. The images 602-628 are in the referenceimage library for the pathogen cell 600. These images are the searchtargets in the pixel data for identifying and locating the pathogencells. These images can be located in the pixel data by the use ofpattern recognition. Pattern recognition for detecting predeterminedimages in a digital data field is well-known technology. An examplepatent describing such technology is U.S. Pat. No. 9,141,885 issued Sep.22, 2015 which patent is incorporated herein by reference in itsentirety.

Referring to FIG. 35 , there are shown views of corresponding shadowimages of red blood cells, which comprise the majority of cells in humanblood. The size of red blood cells can vary, but can be in the range of6-8 microns. In FIG. 35 , left column, there is shown a red blood cell638. A red blood cell has a disc shape with a flattened center where thethickness may be 1-2 microns. Cell 638 with a rotation of 0 degrees canproduce the shadow image 640, with rotation 45 degrees the shadow image642 and with rotation of 90 degrees the shadow image 644. These imagesare included in the image library as being images to be ignored sincethey are different from the bacteria or other pathogen images that aresought to be found.

FIG. 36 shows a white blood cell 648 having a relatively large size anda white blood cell 650 having a smaller size. These cells areessentially spherical so appear approximately the same at all rotationangles. Cell 648 can produce a shadow image 652 and cell 650 can producea shadow image 654. Again, these images 652 and 654 can be included inthe cell library as images to ignore.

A blood platelet cell 660 is shown in FIG. 37 . A platelet is a biconvexdiscoid (lens-shaped) structure, 2-3 micron in greatest diameter. Thisshape is thin at the edge and thickest in the center. At a rotation of 0degrees, a cell 660 can produce a shadow image 662, at a rotation of 45degrees a shadow image 664 and at 90 degrees, a shadow image 666. Aswith the other normal blood cells, these images are used as recognitionof cells to ignore in the image recognition processing operation.

Each of the cells in FIGS. 35, 36 and 37 are shown, for illustration, ata limited number of rotation angles, but the reference library cancontain images representing a finer degree of rotation, for example,every 5 degrees of rotation.

The operation of the present disclosure, in a summary description,includes initially determining the static position of pathogen cells inchannels in the cassette chamber. Next, the pump and a travel time timerare started simultaneously. The pump operation causes the pathogen cellsto move from the initial location toward the processing zone of thechamber. When the travel time expires for a located cell, that pathogencell is then positioned in the venting region of the processing zone,the region having valves in the channel. When the travel time expires,the chamber driver generates voltage waveforms that are applied to thevalve assemblies in the processing zone to activate the correspondingvalves. One valve closes to block fluid flow in the channel, and asecond valve is opened in a vent line from the channel such that a flowsegment of blood (a slug) is driven through a vent line to the sump.This slug of blood includes the previously located pathogen cell. Whenthe vent valve is opened, a small quantity of fluid is vented. A methodof determining the travel time between the identification zone where acell is located and the processing zone where the cell is vented isdescribed in reference to FIGS. 38 and 39 and a logical flow diagram forthis process is shown in FIG. 40 .

Determination of travel times from specific channel zones to ventlocations is shown in FIGS. 38 and 39 . A channel 426 is representativeof each of the channels shown in the chamber in FIG. 15 . The channel426 is divided into a plurality of sequential and contiguous channelzones, including exemplary channel zones 427, 428, 429 and 431. As anexample, the channel 426 can be 8 microns wide and each zone is 6microns long. The channel zones do not have any physical structuremarking the position of each zone, but are defined by longitudinalposition. If, for example, a channel is 2 centimeters long, it will haveapproximately 3333 channel zones. The channel 426 further includesarbitrarily defined sets of channel zones identified as a first window433 of zones and a second window 435 of zones.

An approximation of the flow rate of blood through the channels in thechambers of the cassette 58 can be calculated using the flow rate of thepump 62 and the geometry of the flow lines and chambers of the cassette58. The channel zone 427 is selected to be adjacent the input of thechamber. The location of the first window 433 is determined by use ofthe calculated approximate fluid flow rate of blood in a chamber and issufficiently wide to accommodate the possible error in that flow ratecalculation. The second window 435 is set downstream at a predetermineddistance from the first window 433. A processing zone 437 in channel 426corresponds to the processing zone 250 in FIG. 15 . The flow ratecalibration process described in FIGS. 38 and 39 more accuratelyestablishes the total travel time from each of the channel zones, wherea pathogen cell is initially located, to the valve opening in theprocessing zone, as compared to a flow rate determined by pump rate,tubing size and cassette geometry. The processing zone is the region ofthe channel at a channel opening, such as channel 277, to a valveassembly 287. See FIG. 16 .

Referring to FIG. 39 , there is shown a chart of flow rate of fluidversus time. The pump starts at time t₁ where the fluid velocity iszero. After the pump starts, the fluid velocity increases until itreaches a constant velocity. This is shown as velocity v₁. Depending onphysical configuration, the time to reach constant velocity could be,for example, approximately 0.01 to 0.02 seconds. A time T1 is selectedwhich is larger than the time for the fluid to reach constant velocity.A time T2 is selected which, when added to time T1, is the approximatetravel time from the zone 427 to within the second window 435. The totaltravel time, from zone 427, to the center of the processing zone 437 isTTi, the “i” representing each zone.

The calibration process, shown in FIGS. 38 and 39 , is described indetail in the logic diagram in FIG. 40 . In summary, the process beginswith pumping fluid into the chambers of a cassette and then stopping thepump. The light sensor below a chamber is activated and the light sourceis turned on the illuminate the chambers. Pathogen cells in the channelsof the chamber create shadow images in the pixels of the light sensor.The data from the light sensor is stored in a corresponding memory. See.FIG. 24 . The pixel image data is evaluated by a corresponding processorusing pattern recognition with a reference library to identify andlocate pathogen cells, such as cell 439 in channel zone 427 (see FIG. 38). The pump is activated and when the cell 439 is in the first window433, the light sensor is reset and the light source is activated for ashort flash, for example a millisecond or less, and the shadow image iscreated in the corresponding light sensor. The pixel data is processedby the corresponding chamber processor to identify and locate the cell439, which as shown in this example, is located in channel zone 429. Thelocations of zones 427 and 429 define a distance D1. The fluid is movingat the constant velocity when the cell is imaged at zone 429, but thelight flash is of sufficiently short duration, as compared to the flowrate, such that there is a clear image of the cell. This is essentiallya “stop image” shot. The fluid continues to move until the pathogen cellis in the second window 435 where another flash shot image is taken asjust described. The cell 429 is then determined to be in channel zone431 in window 435.

Further referring to FIGS. 38 and 39 , the distance between zones 429and 431 is a known design parameter. T1 and T2 and distance Dt (for eachchannel zone) are selected in advance. T1 is selected to be less thanthe smallest total travel time. T3 (FIG. 38 ) is the flow time from theend of time T1 to the cell 439 arrival at the center of processing zone437, the opening to the corresponding vent valve. D3 is the distancefrom zone 429 to the center of zone 437. The total travel time from aninitial channel zone to the center of the processing zone is TTi. Theconstant velocity fluid flow rate (Vcv) between zones 429 and 431 isdetermined by the equation: Vcv=D2/T2. Therefore, the total travel time(TTi) from any channel zone to the center of the processing zone 437 is:TTi=T1+T3; T3=D3/Vcv, and therefore:

TTi=T1+(Dt−D1)(T2/D2).

Thus, after the calibration process described above has been performedfor a channel in a chamber, the total travel time TTi can be calculatedfor each channel zone (i) in the identification field of the chamber.The distance Dt is different for each channel zone in a single channel.It is a cassette design parameter. Further, the same calibration processis performed for all of the channels in all of the chambers. Acalibration table is prepared for each chamber that provides the traveltime from each channel zone to the center of the correspondingprocessing zone. In operation, after a pathogen cell is identified inthe detection zone and located in a specific channel zone, the pump isstarted and the pathogen cell moves toward the processing zone and whenthe total travel time, for that specific channel zone, expires, thepathogen cell is located in the processing zone. At that time, a voltageis applied to a first valve assembly in the processing zone to block theflow in the channel and to open a second valve to vent the pathogen cellas it passes through the processing zone. A limited volume of fluidsurrounding the pathogen cell is also vented. In this process, the fluidflow is continuous after the pathogen cell has been initially identifiedand located. After the blood in the chamber has been replaced, the pumpis stopped and the process is repeated.

A logic flow description of the calibration process is shown in FIGS.40A, 40B, and 40C. The calibration process is begun at step 446 at thesystem controller 14. The calibration parameters and data are the pumpdrive time to fill the chambers, for example 15 seconds, first andsecond light source activation times LSRC1 and LSRC2. Values of thesetimes can be, for example, respectively 1 second and 1-5 milliseconds.The cell library is the collection of pathogen images described above.The estimated travel times can be, for example T1=1-2 seconds andT2=4-10 seconds. The start calibration command and the calibrationparameters are downloaded to the master controller 434 from the systemcontroller 14 in step 448.

Continuing reference to FIG. 40 , in step 450, the master controller 434starts the pump 62, runs the pump for the fill time and then stops thepump. Next, in step 452, the master controller 434 resets all of thelight sensors so that they are prepared to receive light from the lightsource 54. In step 454, after the light sensors are reset, the mastercontroller 434 activates the light source 54 for the time period LSRC1and the light sensors receive light after it has passed through thechambers and shadow images of cells in the chambers are created in thepixel data in the light sensors. In step 456, after expiration of thetime period LSRC1, the master controller 434 transfers the image datafrom the light sensors to the corresponding memories. See FIG. 24 . Instep 457, the chamber processor, for each chamber, processes the imagedata by performing pattern recognition with the cell library to identifypathogen cells in the channel zones. In step 458, each chamber processorselects one located pathogen cell for the calibration process. Thespecific location zone for this selected cell is identified. See FIG. 38.

In step 460, the master controller 434 resets all of the light sensors.See zone 427 in FIG. 38 . Next, in step 462, the master controllerconcurrently starts the pump 62 and a calibration timer to runsequential times T1 and T2. At step 463, upon expiration of time T1, thelight source 54 is activated for time period LSRC2. This takes a “stopaction” image of cells in the channels in the first window 433. Thefluid flow rate is slow in comparison to the on time of the light sourceso that a clear image is produced without stopping the fluid flow. Atstep 464, after the time LSRC2 has ended, the master controller 434transfers the pixel data from each light sensor to the correspondingmemory. In step 465, the chamber processors process the image data inthe corresponding memories using the cell library and patternrecognition to identify and locate the cell previously identified in thechannel at the initial channel zone. In step 466, the chamber processordetermines the distance D1 which is between the initial channel zonelocation and the identified location in the first window 433.

In step 467, the master controller 434 resets all of the light sensors.Next, in step 468, when the time period T2 expires, the mastercontroller activates the light source 54 for the time duration LSRC2. Instep 469, when the time period T2 has expired, the master controllertransfers the collected pixel data from each light sensor to thecorresponding memory. In step 470, the chamber processors performpattern recognition on the pixel data for pattern recognition and usingthe cell library as reference data, to locate the previously identifiedpathogen cell previously identified in the first window. Next, in step471 the chamber processor determines the distance D2 which is thedistance between the identified cell locations in the first and secondwindows. In step 472, the master controller 434 stops the pump.

Next, in step 473, the chamber processor calculates the fluid velocitybetween the two locations in the windows, using distance D2 and time T2.See FIG. 38 . With this data the chamber processer determines the totaltravel time TTi for each channel zone (i) to the center of theprocessing zone. The travel times are determined for all channels ineach chamber. In step 474, the chamber processors transfer the totaltravel time table of values for each chamber to the master controller434. In step 476, the master controller transfers all of the travel timetables for all of the chambers to the system controller 14 and reportscompletion of the calibration process. In step 478, the systemcontroller 14 displays an end of calibration report on its displayscreen and ends the calibration process.

By calibrating the travel time of each initially detected pathogen cellto the center of the processing zone, the duration of the valve opentime can be limited so that the minimum volume of fluid is vented withthe pathogen cell. If the predicted total travel time number were to beless accurate, the vented fluid volume in the processing zone would needto be larger to assure that the pathogen cell is in the processing zonewhen the vent valve is open. Alternatively, the travel times can becalculated by use of ump flow rate and the parameters of the flow tubesand chambers.

An operation process for an embodiment of the present invention is shownby the logic flow in FIGS. 41A, 41B and 41C. This process utilizesapparatus shown and described in the prior text and figures. The processbegins with a start command, for example, from an operator, at thesystem controller 14 in step 480. The system controller 14 downloadsdata and processing parameters, step 482, and a start command is sent tothe master controller 434. The processing data and parameters include:

-   -   1. Pathogen image cell library.    -   2. Initial pump flow time and pump cycle on and off times. This        can be, for an example, an initial flow time of 20 seconds to        completely fill all of the chambers. After the start, a flow and        processing time of 10 seconds with a stop time of 2 seconds for        identification of pathogen cells. The 2 second stop with 10        second flow procedure is repeated until the processing is        completed.    -   3. A light generation time, for example, in a range of 20 to 100        milliseconds.    -   4. A light sensor collection time of, for example, within a        range of 5 to 50 milliseconds.    -   5. Voltage waveforms and timing for application to the        processing zone valve assemblies.    -   6. Alignment data for each sensor array.    -   7. Travel Time Table for each channel of each chamber.    -   8. Total processing time, for example, in the range of 6-24        hours.

In step 484, the master controller 434 sends certain data and processingparameters to the chamber processors. This includes the pathogen imagelibrary, the voltage waveforms and timing for the valve assemblies inthe processing zone, the alignment data for sensor arrays and the totaltravel time tables for each chamber. In step 486 the voltage waveformsand travel time tables are transferred from the chamber processors tothe chamber drivers for each chamber.

In step 488, the master controller 434 runs the pump for the initialpump flow time to fill the chambers and then stops the pump. The mastercontroller 434 also starts a total processing time timer. In step 490,the master controller resets all of the light sensor arrays so they areprepared to receive light. In step 492, the master controller 434activates the light source 54 for the light generation time. Next, instep 494, the light sensors are activated to collect light for the pixellight collection time. In step 496 the collected pixel light data istransferred from the sensor arrays to a corresponding memory. In step498, the master controller 434 commands each chamber processor toperform pattern recognition on the stored pixel data using the pathogencell library and to locate each identified pathogen cell in each chamberof the corresponding chamber. In step 500, each chamber processorperforms the pattern recognition and generates a listing of the pathogencell locations in each channel of the corresponding chamber. Eachidentified pathogen cell is in a channel zone, see FIG. 38 , for examplezone 428. The chamber processor also adjusts for any misalignmentbetween cassette and sensor array with the alignment data. In step 502each chamber processor, by use of the downloaded travel time table,determines the total travel time for each identified pathogen cell fromits identified channel zone location to the vent line at the center ofthe processing zone.

Further referring to FIG. 41C, in step 504 the determined travel timesfor each identified pathogen cell and the corresponding channel aretransferred to the corresponding chamber drivers. The chamber driversare also commanded to set the valves to the initial state 526 as shownin FIG. 42 . Further referring to FIG. 42 , signal 512 is applied,selectively, by the chamber driver 318 to each of the channel valves 275and signal 513 is applied, selectively, to the vent valves 276.

Further in FIG. 41B, in step 504 the chamber processors report thecompletion of the data transfer to the master controller 434. In step505 of FIG. 41C, the chamber drivers apply the initial state pulses 526(FIG. 42 ) to all of the channel valves and vent valves such that thechannel valves allow fluid to flow in the channels and the vent valvesblock fluid flow in all of the vent lines.

In FIG. 42 , the voltage −V causes the valve element to retract, thevoltage +V causes the valve element to extend.

The data transfer and command in step 504 is done via the optical datalink from the chamber processor to the chamber driver, see FIG. 24 ,light transmitter 409 and FIG. 21 , light receiver 348. In step 506 ofFIG. 41C, the master controller 434 receives the data transfercompletion reports for all chamber processors and then activates thepump 62 and sends chamber driver activation commands to all of thechamber processors.

In step 508, the chamber processors send activation commands to thecorresponding chamber drivers via the optical link. In step 510, inresponse to the activation command, each chamber driver starts thetiming for the total travel times for the identified pathogen cells ineach channel of each holding chamber. When a total travel time iscompleted for a channel, the corresponding chamber driver generatesvoltage signals which are applied to the control lines in that channelin the processing zone, for example, control lines 284 shown in FIG. 17. In FIG. 42 there are shown waveforms 512 and 513. These waveforms areshown as a function of time “t” along the horizontal scale. The peakpositive value is +V, which can be, for example, 10 volts. Thesewaveforms are applied to the lines 284 shown in FIG. 17 . The group oflines 284 have a single wire pair going from the driver 318 to each ofthe valve assemblies. The pair of lines provide a differential voltage.Further referring to FIG. 42 , signal 512 is applied selectively to thechannel valves 275 and signal 513 is selectively applied to the ventvalves 276.

In FIG. 42 , the initial state 526 has a negative pulse for signal 513which retracts the valve element for each of the channel valves to allowfluid to flow through the channels. For signal 513 in the initial state526, the positive pulse causes each of the valve elements of the ventvalves 276 to extend and thereby close the vent lines. A vent cycle 528is initiated when each total travel time for a located pathogen cell hasexpired. The vent cycle for signal 512 (channel valve) has a positivepulse that extends the valve element to block the fluid flow through thecorresponding channel Signal 513 has a negative pulse which causes thecorresponding vent valve to retract and allow the fluid to move up thevent line from the flow channel and through the vent line to the sump25. At the end of the vent cycle 528, the negative pulse in signal 512causes the channel valve element to retract and allow fluid flow throughthe channel and concurrently the positive pulse in signal 513 causes thevent valve element to extend and block fluid flow through the vent line.The vent cycle 528 duration is the parameter “vent time.”

Continuing reference to FIG. 41C, at step 514, the master controller 434turns the pump 62 off upon expiration of the pump cycle time. This timeis set to be long enough for all of the pathogen cells to flow from themost distant portion of the detection zone to the processing zone. Thatis, longer than the longest total travel time. When the pump 62 has beenturned off, the blood previously in the chambers has been removed andreplaced with a new volume of blood for processing. Following step 514the master controller performs the question step 516 to determine if thetotal processing time has been reached. If the answer to this questionis “NO”, the exit 518 is taken and operations are transferred to step490 to repeat the overall processing operation. If the answer to thestep 516 question is “YES”, exit 520 is taken to step 522. If this exitis taken, the total processing time has elapsed. In step 522, the mastercontroller 434 terminates the processing operation and sends a reportthereof to the system controller 14. In step 524 the system controller14 ends the processing operation and sends a report thereof to itsdisplay terminal.

One embodiment described above has 30 chambers in a single cassette witha sensor, a chamber processor and memory for each chamber. However,embodiments can be implemented having different configurations whichoperate as described above. Further, the embodiments can be scaled bythe number of chambers and/or flow rate through a chamber and/or dataprocessing speed to provide a desired overall flow rate for bloodprocessing. Non-limiting example embodiments are as follows:

-   -   1. 10 chambers each 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor with a single processor and memory        serving all 10 chambers.    -   2. 10 chambers each 4.0 cm×4.0 cm, each chamber having a        corresponding light sensor, processor and memory.    -   3. 30 chambers 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor, and a single processor and memory        serving all 30 chambers.    -   4. 30 chambers divided into a separate 15 chamber Group A and 15        chamber Group B with a sensor for each chamber and a single        processor and single memory for each group.    -   40 chambers each 2.0 cm×2.0 cm and each chamber having a        corresponding light sensor, and a processor and memory for each        set of 10 chambers.    -   6. 100 chambers 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor, processor and memory.    -   7. 100 chambers 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor and having one memory and one        processor for each 10 chambers.

Although several embodiments of the invention have been illustrated inthe accompanying drawings and described in the foregoing DetailedDescription, it will be understood that the invention is not limited tothe embodiments disclosed but is capable of numerous rearrangements,modifications and substitutions without departing from the scope of theinvention.

What is claimed is:
 1. A method for processing of blood having pathogencells therein, comprising the steps of: filling a chamber with saidblood, said chamber having opposing transparent walls, directing lightthrough said chamber walls, detecting light transmitted through saidchamber walls to produce a sensor image having shadow images therein ofones of said pathogen cells present in said chamber, performing patternrecognition on said sensor image by use of an image library having oneor more images of said pathogen cells to identify and locate pathogencells in said chamber, moving said blood through said chamber after saidstep of directing said light, and venting said located pathogen cellsfrom said chamber after said step of moving said blood through saidchamber has started.
 2. A method for processing of blood having pathogencells therein as recited in claim 1 wherein said step of detecting lighttransmitted through said chamber walls is performed with said blood in anonmoving state in said chamber.
 3. A method for processing of bloodhaving pathogen cells therein as recited in claim 1 including a step ofconducting said vented pathogen cells through a vent line to a sump forcollecting said vented pathogen cells therein.
 4. A method forprocessing of blood having pathogen cells therein as recited in claim 1wherein all of the steps are repeated sequentially until a predeterminedtime expires.
 5. A method for processing of blood having pathogen cellstherein as recited in claim 1 wherein said step of venting is performedby a plurality of valves coupled to said chamber, each said valveopening in response to a control signal derived from the determinedlocation of a one of said pathogen cells.
 6. A method for processing ofblood having pathogen cells therein as recited in claim 1 wherein saidsteps of filling and moving are performed by a blood pump that isexternal to said chamber.
 7. A method for processing of blood havingpathogen cells therein as recited in claim 1 wherein said step ofventing said located pathogen cells from said chamber includes passingsaid vented pathogen cells through a vent line to a collection sump. 8.A method for processing of blood having pathogen cells thereincomprising the steps of: filling a chamber with said blood and holdingsaid blood in said chamber in a nonmoving state, said chamber havingopposing transparent walls, directing light through said opposingchamber walls, detecting light transmitted through said chamber walls toa light sensor for producing a sensor image having shadow images thereinof ones of said pathogen cells present in said chamber, said detectingperformed while said blood in said nonmoving state, performing patternrecognition on said sensor image by use of an image library having oneor more images of said pathogen cells to identify and locate pathogencells in said chamber, determining respectively for each of saididentified and located pathogen cells a corresponding timing signal,after said step of detecting light, start said blood moving through saidchamber, and after said step of start said blood moving has begun,activating each of a plurality of valves in response to said timingsignals to open a one of the valves for a one of said pathogen cellscorresponding to the timing signal applied to the one valve, such thatthe pathogen cell corresponding to the timing signal is vented out ofthe chamber through the valve.
 9. A method for processing of bloodhaving pathogen cells therein as recited in claim 8 including the stepof conveying said pathogen cells which have passed through said valvesinto a vent line which is exterior to said chamber.
 10. A method forprocessing of blood having pathogen cells therein as recited in claim 8including a step of conveying said pathogen cells which have passedthrough said valves into a vent line which is exterior to said chamberand further conveying said pathogen cells which have passed through saidvalves into a sump.
 11. A method for processing of blood having pathogencells therein as recited in claim 8 wherein all of the steps arerepeated sequentially until a predetermined time expires.
 12. A methodfor processing of blood having pathogen cells therein as recited inclaim 8 wherein the amplitude of each of said timing signals isdependent on the distance from the location of the corresponding locatedpathogen cell to the location of a one of said valves which is activatedby the timing signal.
 13. A method for processing of blood havingpathogen cells therein as recited in claim 8 wherein each of said valvesis opened by an electrical actuator that receives a one of said timingsignals.
 14. A method for processing of blood having pathogen cellstherein as recited in claim 8 wherein said step of directing lightthrough said opposing chamber walls includes a step of generating anarea of collimated light that is directed normal to surfaces of saidchamber walls.
 15. A method for processing of blood having pathogencells therein comprising the steps of: filling a chamber with said bloodand then holding said blood in said chamber in a nonmoving state, saidchamber having a blood input port, a blood output port, opposingtransparent walls, and a plurality of parallel channels extendingbetween said input port and said output port, said channels closed bysaid opposing transparent walls, directing light through said opposingchamber walls, detecting light transmitted through said chamber walls bya light sensor to produce a sensor image having shadow images therein ofones of said pathogen cells present in said chamber, said detectingperformed while said blood is in said nonmoving state, performingpattern recognition on said sensor image by use of an image libraryhaving one or more images of said pathogen cells to identify and locatepathogen cells in said chamber, after said step of directing light hasbeen completed, initiate moving said blood through said channels in thedirection of said chamber output port, and selectively opening each of aplurality of valves corresponding respectively to said channels when aone of said identified pathogen cells is proximate a one of said valvesto vent the proximate pathogen cell through the valve to exterior ofsaid chamber.
 16. A method for processing of blood having pathogen cellstherein as recited in claim 15 wherein the step of to vent the proximatepathogen cell through the valve to exterior of said chamber includesventing a quantity of blood which includes said proximate pathogen cellthrough said corresponding valve.
 17. A method for processing of bloodhaving pathogen cells therein as recited in claim 15 wherein all of thesteps are repeated sequentially until a predetermined time expires. 18.A method for processing of blood having pathogen cells therein asrecited in claim 15 including the step of conveying the cells which havebeen vented through said valves through a vent line to a sump.
 19. Amethod for processing of blood having pathogen cells therein as recitedin claim 15 wherein the step of selectively opening each of a pluralityof valves comprises operating said valves in response to timing signalsproduced by a processor which detected the locations of said identifiedpathogen cells.
 20. A method for processing of blood having pathogencells therein as recited in claim 15 wherein pathogen cells located in aparticular one of said channels are vented to the exterior of saidchamber through a one of said valves coupled to said particular one ofsaid channels.